Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli. Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all components of chronic bronchial asthma.
An alternative to the "mediator approach" is to regulate the activity of cells responsible for the pathophysiology of asthma. Cyclic AMP (cAMP, adenosine cyclic 3',5'-monophosphate) modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. An elevation of cAMP would produce beneficial effects including: (1) airway smooth muscle relaxation, (2) inhibition of mast cell mediator release, (3) suppression of neutrophil degranulation, (4) inhibition of basophil degranulation, and (5) inhibition of monocyte and macrophage activation. Cyclic AMP has been shown to mediate cellular responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
One potential means to regulate the activity of cells responsible for the pathophysiology of asthma is to control the intracellular levels of cyclic AMP. Cellular cAMP levels are elevated when an appropriate agonist binds to particular cell surface receptors, thereby activating adenylate cyclase to convert Mg.sup.+2 -ATP to cAMP at an accelerated rate. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (cyclic nucleotide phosphodiesterase hereinafter "PDE"s). Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
It has been shown that a distinct PDE isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. The beneficial effects of PDE IV inhibition are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids. Thus, PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E.sub.2 and prostacyclin (both activators of adenylate cyclase) are elevated. PDE IV inhibitors offer a unique approach to the pharmacotherapy of bronchial asthma, and possess significant therapeutic advantages over agents currently on the market The compounds of this invention have the ability to inhibit PDE IV.
The compounds of this invention also inhibit the production of TNF, a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of undesirable physiological conditions, such as diseases , and including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, human acquired immune deficiency syndrome (ADS), cachexia secondary to AIDS, AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified: HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into a T lymphocyte requires prior T lymphocyte activation. Once an activated T lymphocyte has been infected with HIV, the T lymphocyte must be maintained in an activated state in order to permit HIV gene expression and/or HIV replication.
Cytokines, including TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus replication as playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity in an HIV-infected individual, such as by inhibition of TNF production, aids in limiting the maintenance of T cell activation, and thereby mitigates the progression of HIV infection to previously uninfected cells. When HIV infection of previously uninfected cells is diminished, a slowing or elimination of the progression of immune dysfunction caused by HIV infection results.
Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in the maintenance of HIV infection. These cells, like T cells, are targets for viral replication, where the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted. TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214, 1990].